PROJECT SUMMARY/ABSTRACT In North America, advanced biomedical HIV prevention and treatment technologies (e.g., pre-exposure prophylaxis, simplified antiretroviral therapy regimens), systems-level innovations (e.g., HIV Treatment as Prevention), and interventions to co-manage HIV/AIDS and co-morbidities (e.g., integrated HIV/AIDS care) are being harnessed pursuant to the goal of both ending and reducing the overall health burden associated with HIV/AIDS. To date, there has been a lack of research into the acceptability, feasibility, and implementation of emerging and prospective (e.g., long-acting antiretroviral therapy, HIV vaccines) interventions among people who use drugs (PWUD), despite continuing disparities in HIV-related outcomes among drug-using populations. As a consequence, drug-using populations might not fully benefit from advancements in HIV prevention, treatment, and care that will represent a crucial component of the global response to HIV/AIDS over the next decade. The purpose of this application is to apply an ethno-epidemiological approach to examine individual, social, structural, and environmental influences on the acceptability, feasibility, and implementation of emerging and prospective biomedical, systems-level, and programmatic interventions to prevent and treat HIV/AIDS and manage co-morbidities among PWUD. The proposed study is nested within a larger program of research that includes three NIDA-funded, longitudinal cohort studies comprised of HIV-negative and HIV- positive PWUD and drug-using street-involved youth (SY) in Vancouver, Canada. Thus, this approach offers a `value-added' opportunity to harness these cohort studies to undertake epidemiologically-informed sampling and targeted recruitment of PWUD and collect ethnographic and qualitative data that can be triangulated with quantitative clinical and behavioral data. Extending our ethno-epidemiological research to examine emerging and prospective HIV prevention and treatment interventions, as well as the management of co-morbidities, will result in a more complete understanding of influences on these interventions among PWUD than is possible through epidemiological research alone. Vancouver is ideally suited for the proposed research for several reasons. The city has been the site of ongoing innovation with respect to novel and combination HIV prevention, treatment, and care interventions, with approaches piloted here often implemented in other settings (e.g., HIV Treatment as Prevention). Further, Vancouver presents unique opportunities to undertake research into the acceptability, feasibility, and implementation of emerging and prospective interventions and subsequent impacts on HIV-related outcomes (e.g., ART adherence, virological outcomes) in a `real world' setting, without the confounding influence of health insurance. The proposed research is aligned with the NIH Office of AIDS Research Priorities and Guidelines (2015) and the 2017 Trans-NIH Plan for HIV-Related Research, and will help inform the optimization and scale-up of these interventions in Canada, the United States, and other high-income settings.